The present invention relates to the novel combination therapy of valerian-related products and valerian extracts in combination together with anti-inflammatory agents such as the non-steroidal anti-inflammatory drugs (NSAIDs) to elicit greater, improved relief from pain and muscle tension due to stress or injury. More particularly, the invention provides therapeutic combinations of isovaleramide, isovaleric acid, and/or related compounds with NSAIDs, such as ibuprofen, and methods for using these combinations for treating patients suffering from acute lower back pain.
Many agents currently employed in the treatment of muscle pain, such as lower back pain, reduce inflammation, yet provide no decrease in muscle tone, which is a significant component of acute muscle pain. Likewise, many of the currently employed agents that elicit a decrease in muscle tone, for example, benzodiazepines, do not reduce inflammation.
It is apparent, therefore, that compositions that can both reduce inflammation and elicit a decrease in muscle tone are greatly to be desired. It also is apparent that improved methods for treating pain and muscle tension are highly desirable.
Accordingly, it is an object of the present invention to provide a therapeutic combination of valerian extract and/or valerian-related compounds together with at least one NSAID for the improved relief from pain and muscle tension due to stress or injury.
It also is an object of the present invention to provide a method for alleviating one or more symptoms associated with acute muscle pain that is ameliorated by means of a decrease in muscle tone.
It is another object of the present invention to provide a novel combination therapy for the treatment of treating a pathology that is ameliorated by a decrease in muscle tone and a reduction in inflammation.
In accomplishing these and other objectives, there has been provided, according to one aspect of the present invention, the use of a combination of: (a) at least one non-steroidal anti-inflammatory compound, and; (b) at least one compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, a pharmaceutically acceptable amide of isovaleric acid and a compound having the structure: 
where A=H, CH3 or OH,
B=H, OH, or CH3,
X=CH2, CHCH3, C(CH3)2, xe2x80x94Oxe2x80x94, CH(OH)xe2x80x94, or xe2x80x94CH2Oxe2x80x94,
Y=xe2x80x94COxe2x80x94, or xe2x80x94SO2xe2x80x94, and
Z=H, CH2CO2H, or CH2CONH2 
and where the compound is selected from the group consisting of 2-methyl isovaleramide, 3-methylisovaleramide, 2,2-dimethylisovaleramide, 2,3-dimethylisovaleramide, 4-methylisovaleramide, 2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide, 2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide, 4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide, 2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, 2-methyl-1-propyl sulfonamide, 1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate, isopropyl carbamate, and isobutylcarbamate, in the preparation of a pharmaceutical formulation for use in a method of treating a pathology that is ameliorated by a decrease in muscle tone and a reduction in inflammation, whereby at least one symptom of that pathology is alleviated.
In accordance with another aspect of the invention, the pathology is selected from the group consisting of acute muscular aches, strains, and sprains which occur from a localized, external insult to a particular muscle or muscle group outside of, or peripheral to, the CNS. In one embodiment, the pathology is lower back pain, and in another embodiment, the pathology is ameliorated by a decrease in inflammation, pain, and muscle tone.
In accordance with yet another aspect of the invention, the non-steroidal anti-inflammatory compound is selected from the group consisting of aspirin, a non-steroidal anti-inflammatory acetic acid, a fenamate, an oxicam, and a non-steroidal anti-inflammatory propionic acid. In one embodiment, the non-steroidal anti-inflammatory compound is selected from the group consisting of sodium salicylate, acetaminophen, phenacetin, ibuprofen, ketoprofen, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone, etodolac, nabumetone, tenidap, alcofenac, antipyrine, amimopyrine, dipyrone, animopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen, meclofenamic acid, mefenamic acid, niflumic acid, salidifamides, sulindac, suprofen, tolmetin, nabumetone, tiaramide, proquazone, bufexamac, flumizole, tinoridine, timegadine, dapsone, diflunisal, benorylate, fosfosal, fenclofenac, etodolac, fentiazac, tilomisole, carprofen, fenbufen, oxaprozin, tiaprofenic acid, pirprofen, feprazone, piroxicam, sudoxicam, isoxicam, celecoxib, Vioxx(copyright) and tenoxicam. In another embodiment, the non-steroidal anti-inflammatory compound is selected from the group consisting of aspirin, sodium salicylate, acetaminophen, ibuprofen, ketoprofen, and naproxen.
In accordance with still another aspect of the invention, the composition comprises a pharmaceutically acceptable amide of isovaleric acid, where the amide is isovaleramide. In preferred embodiments, the composition comprises isovaleramide together with ibuprofen, aspirin, acetaminophen, acetylsalicylic acid, naproxen, or ketoprofen.
In accordance with a still further aspect of the invention there has been provided a use of an extract of Valerianaceae, cramp bark, black haw, or hops in combination with at least one non-steroidal anti-inflarnmatory compound in the preparation of a pharmaceutical formulation for use in a method of treating acute muscular aches, strains, and sprains which occur from a localized, external insult to a particular muscle or muscle group outside of, or peripheral to, the CNS wherein the extract comprises at least one compound that is hydrolyzed in vivo to yield isovaleric acid or isovaleramide. In particular embodiments the non-steroidal anti-inflammatory compound is ibuprofen, aspirin, acetaminophen, acetylsalicylic acid, naproxen, or ketoprofen.
In accordance with yet another aspect of the invention there has been provided a pharmaceutical composition comprising (a) at least one non-steroidal anti-inflammatory compound, and; (b) at least one compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, a pharmaceutically acceptable amide of isovaleric acid and a compound having the structure: 
where A=H, CH3 or OH,
B=H, OH, or CH3,
X=CH2, CHCH3, C(CH3)2, xe2x80x94Oxe2x80x94, CH(OH)xe2x80x94, or xe2x80x94CH2Oxe2x80x94,
Y=xe2x80x94COxe2x80x94, or xe2x80x94SO2xe2x80x94, and
Z=H, CH2CO2H, or CH2CONH2 
and where that compound is selected from the group consisting of 2-methyl isovaleramide, 3-methylisovaleramide, 2,2-dimethylisovaleramide, 2,3-dimethylisovaleramide, 4methylisovaleramide, 2,4-dimethylisovaleramide, 3,4-dimethylisovaleramide, 2,2,4-trimethylisovaleramide, 3-hydroxyisovaleramide, 4-hydroxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide, 2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, 2-methyl-1-propyl sulfonamide, 1-methylethyl sulfamate, 2-methyl-1-propyl sulfamate, isopropyl carbamate, and isobutylcarbamate, together with a pharmaceutically acceptable diluent, excipient, or carrier.
In one embodiment, the non-steroidal anti-inflammatory compound is selected from the group consisting of aspirin, a non-steroidal antiinflammatory acetic acid, a fenamate, an oxicam, and a non-steroidal anti-inflammatory propionic acid. In another embodiment, the non-steroidal anti-inflammatory compound is selected from the group consisting of sodium salicylate, acetaminophen, phenacetin, ibuprofen, ketoprofen, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone, etodolac, nabumetone, tenidap, alcofenac, antipyrine, amimopyrine, dipyrone, animopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen, meclofenamic acid, mefenamic acid, niflumic acid, salidifamides, sulindac, suprofen, tolmetin, nabumetone, tiaramide, proquazone, bufexamac, flumizole, tinoridine, timegadine, dapsone, diflunisal, benorylate, fosfosal, fenclofenac, etodolac, fentiazac, tilomisole, carprofen, fenbufen, oxaprozin, tiaprofenic acid, pirprofen, feprazone, piroxicam, sudoxican, isoxicam, celecoxib, Vioxx(copyright) and tenoxicam. In yet another embodiment, the non-steroidal anti-inflammatory compound is selected from the group consisting of aspirin, sodium salicylate, acetaminophen, ibuprofen, ketoprofen, and naproxen.
In a particular embodiment, the composition comprises a pharmaceutically acceptable amide of isovaleric acid, where that amide is isovaleramide. In other embodiments, the composition comprises isovaleramide together with aspirin, sodium salicylate, acetaminophen, ibuprofen, ketoprofen, or naproxen.
In accordance with a still further aspect of the invention, there has been provided a pharmaceutical composition comprising an extract of Valerianaceae, cramp bark, black haw, or hops and at least one non-steroidal anti-inflammatory compound, together with a pharmaceutically acceptable diluent, excipient, or carrier. In particular embodiments the non-steroidal anti-inflammatory compound is aspirin, sodium salicylate, acetaminophen, ibuprofen, ketoprofen, or naproxen.
Other objects, features, and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.